Azelastine hydrochloride has been used as an anti-allergy agent in medicinal treatments for bronchial asthma, allergic rhinitis, hives, eczema, dermatitis, atopic dermatitis, cutaneous pruritus, pruriqo, etc.
Generally, the absorption of basic medicines is thought to be high for non-dissociation types and low for dissociation types. For example, in Drug Metabolism Review 8(2),223-233, 1978, it is shown that the percutaneous penetration speed of the basic medicine scopolamine is in direct proportion to the pH, and thus, since azelastine is a basic medicine, its absorption may also be expected to be favorable in direct proportion to the pH of the preparation. However, the acid dissociation constant (pKa) of azelastine is approximately 9.5. Thus, to make the proportion of non-dissociation type molecules 50%, it is necessary to adjust the pH of the preparation to 9.5, differing vastly from the physiological pH of the skin and membranes. Further, in an aqueous preparation, the non-dissociation type molecules of azelastine form crystalline hydrates of poor solubility. This causes precipitation, even if the pH and eventually the proportion of the non-dissociation type molecules is increased. Therefore, it is difficult to obtain a homogeneous preparation of azelastine.
In order to prevent precipitation of crystals in the preparation, previously known methods have included the step of adding solvents in which the crystals are readily soluble, or adding a surface active agent to solubilize the non-dissociation type medicine, or adding a water soluble polymer to suppress crystal growth.
Also, techniques of raising the percutaneous absorbability of azelastine hydrochloride have been reported in Japanese Patent publication (KOKAI) HEI 2-288827 and Japanese Patent Application SHO 63-278108. The former is characterized by the addition of an alkylglycerine to the preparation, and the latter is characterized by incorporation of a lactic acid ester of an aliphatic alcohol, such as, for example, cetyl lactate, myristyl lactate, lauryl lactate, and/or a fatty acid monoglyceride of 8 to 12 carbon atoms.
Further, in Japanese Patent publication (KOKAI) SHO 61-254532, a method is disclosed wherein a cationic water soluble medicine and an acidic oil soluble substance are combined to increase the percutaneous absorbability of the medicine. Another known general method for increasing the percutaneous and mucosal absorbability increases the amount of the main ingredient by maximizing its thermodynamic activity in the vehicle.
As described previously the producing of crystalline hydrate of azelastine gives rise to such an undesirable problem that the content of azelastine is heterogeneous, the absorbability of the medicine is lowered and the crystal thereof is changed into an undesirable form during administration.
Also, azelastine hydrochloride has a low solubility in solvents which may be used in pharmaceutical compositions, and thus precipitation of crystals cannot be prevented by addition of a solvent. In order to prevent the production of hydrates by addition of a surface active agent, it is necessary to use the surface active agent at a high concentration in the mixture, which can cause irritation of the skin or membrane. Further, it was not possible to suppress the production of hydrates of azelastine hydrochloride through the addition of a water soluble polymer. The alkyl glycerines disclosed in Japanese Patent publication (KOKAI) HEI 2-288827 are not commercially available and are difficult to obtain. Also in Japan there is as yet no example thereof as an external application and its safety has not been established. Thus, further research is necessary before it can come into actual use. With the technique disclosed in Japanese Patent publication (KOKAI) SHO 63-278108, when the amount of azelastine hydrochloride is high compared to the base, there is a marked improvement in the percutaneous absorbability thereof. On the other hand, when the amount is low, the azelastine hydrochloride disperses in the base, causing the disadvantage of poor percutaneous absorbability. Azelastine hydrochloride is a cationic drug, but no increase in absorbability was observed with the technique disclosed in Japanese Patent publication (KOKAI) SHO 61-254532. Also, if the amount of the drug in the vehicle is increased with consideration to the solubility of the drug in the vehicle, it is easy to increase the percutaneous absorbability. However, the many disadvantages in such a case include a rise in production cost, an increase in the danger of misuse of the preparation, and irritation of the skin due.
The inventors of the present invention carried out diligent research to overcome the above mentioned disadvantages, and succeeded in finding a solution through the method described below, by which the present invention was completed.